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WO2012138981A2 - Nouveaux intermédiaires et procédés pour la préparation du ticagrelor - Google Patents

Nouveaux intermédiaires et procédés pour la préparation du ticagrelor Download PDF

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Publication number
WO2012138981A2
WO2012138981A2 PCT/US2012/032497 US2012032497W WO2012138981A2 WO 2012138981 A2 WO2012138981 A2 WO 2012138981A2 US 2012032497 W US2012032497 W US 2012032497W WO 2012138981 A2 WO2012138981 A2 WO 2012138981A2
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Prior art keywords
compound
alkyl
optionally substituted
formula
aryl
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WO2012138981A3 (fr
Inventor
Vinod Kumar Kansal
Dhirenkumar MISTRY
Sanjay Vasoya
Ghanshyam PANDEY
Amit Taneja
Pramod Kadappa SHINDEY
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Teva Pharmaceutical Industries Ltd
Teva Pharmaceuticals USA Inc
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Teva Pharmaceutical Industries Ltd
Teva Pharmaceuticals USA Inc
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Priority to EP12723973.9A priority Critical patent/EP2694514A2/fr
Priority to BR112013025680A priority patent/BR112013025680A2/pt
Priority to CA2832570A priority patent/CA2832570A1/fr
Priority to US14/009,788 priority patent/US9056838B2/en
Publication of WO2012138981A2 publication Critical patent/WO2012138981A2/fr
Anticipated expiration legal-status Critical
Publication of WO2012138981A3 publication Critical patent/WO2012138981A3/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05B—SPRAYING APPARATUS; ATOMISING APPARATUS; NOZZLES
    • B05B1/00—Nozzles, spray heads or other outlets, with or without auxiliary devices such as valves, heating means
    • B05B1/14—Nozzles, spray heads or other outlets, with or without auxiliary devices such as valves, heating means with multiple outlet openings; with strainers in or outside the outlet opening
    • B05B1/16—Nozzles, spray heads or other outlets, with or without auxiliary devices such as valves, heating means with multiple outlet openings; with strainers in or outside the outlet opening having selectively- effective outlets
    • B05B1/1627—Nozzles, spray heads or other outlets, with or without auxiliary devices such as valves, heating means with multiple outlet openings; with strainers in or outside the outlet opening having selectively- effective outlets with a selecting mechanism comprising a gate valve, a sliding valve or a cock
    • B05B1/1636—Nozzles, spray heads or other outlets, with or without auxiliary devices such as valves, heating means with multiple outlet openings; with strainers in or outside the outlet opening having selectively- effective outlets with a selecting mechanism comprising a gate valve, a sliding valve or a cock by relative rotative movement of the valve elements
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the invention encompasses improved processes for preparing Ticagrelor and new intermediates useful for manufacturing Ticagrelor.
  • Ticagrelor is currently marketed in Europe under the trade name BRILIQUE TI BRILIQUETM is purportedly a reversibly binding oral P2Y12 ADP receptor antagonist.
  • Ticagrelor can be obtained by a process as shown in the following scheme, as described in PCT Publication No. O00034283 :
  • This step has only about 40% conversion and produces a problematic triol byproduct, which can't be removed by crystallization because intermediate (12) is not a solid.
  • Another potential problem with this step is that the methyl 2-(trifluoiOmethylsulfonyloxy)acetate reagent used therein is not commercially available and must be prepared using a reagent such as triflic anhydride, which is both expensive and hazardous.
  • the final step of deprotection of the diol to produce Ticagrelor results in substantial racemization of the cyclopropyl amine.
  • the present invention provides improved processes for preparing Ticagrelor.
  • the invention also provides novel compounds. These compounds can be used as intermediates in the process for preparing Ticagrelor.
  • the present invention encompasses improved processes for the preparation of Ticagrelor.
  • acyl means a radical of the general formula -C(0)-R, wherein -R is hydrogen or hydrocarbyl.
  • R is alkyl
  • the acyl group may be, for example, acetyl (-C(0)CH 3 ), propionyl (-C(O)Et), benzoyl (-C(0)C 6 H 5 ), phenylacetyl (-C(0)CH 2 C 6 H 5 ).
  • alkoxy/aryloxycarbonyl means a radical of the general formula -OC(0)-R, wherein R is a hydrocarbyl group, such as a C1 alkyl or a C ⁇ -w aryl. or a C7 2 arylalkyl group for example carboethoxy (-C0 2 Et), carbomethoxy (-C0 2 Me) and benzyloxycarbonyl (-CO 2 BZ).
  • alkyl by itself or as part of another substituent means, unless otherwise stated, a straight, branched or cyclic chain hydrocarbon radical, including di- and multi-radicals, having the number of carbon atoms designated (i.e. Ci- means one to six carbons) and includes straight, branched chain or cyclic groups. Examples include: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, hexyl, cyclohexyl and cyclopropylmethyl.
  • alkylene by itself or as part of another substituent means, unless otherwise stated, a divalent straight, branched or cyclic chain hydrocarbon radical.
  • alkoxy employed alone or in combination with other terms means, unless otherwise stated, an alkyl group having the designated number of carbon atoms, as defined above, connected to the rest of the molecule via an oxygen atom, such as, for example, methoxy, ethoxy, 1-propoxy, 2-propoxy (isopropoxy) and the higher homologs and isomers.
  • amine refers to radicals of the general formula -NRR', wherein R and R' are independently selected from hydrogen or a hydrocarbyl radical, or wherein R and R' combined form a heterocycle.
  • amino groups include: -NH 2 , methyl amino, diethyl amino, anilino, benzyl amino, piperidinyl, piperazinyl and indolinyl.
  • carbamyl means the group -C(0)NRR', wherein R and R 1 are independently selected from hydrogen or a hydrocarbyl radical, or wherein R and R' combined form a heterocycle.
  • Examples of carbamyl groups include: -C(0)NH2 and -C(0)N(CH 3 ) 2 .
  • cycloalkyl refers to rmg-containing alkyl radicals. Examples include cyclohexyl, cyclopentyl, cyclopropyl methyl and norbornyl
  • heteroalkyl by itself or in combination with another term means, unless otherwise stated, a stable straight or branched chain radical consisting of the stated number of carbon atoms and one or two heteroatoms selected from O, N, and S, and wherein the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized.
  • the heteroatom(s) may be placed at any position of the heteroalkyl group, including between the rest of the heteroalkyl group and the fragment to which it is attached, as well as attached to the most distal carbon atom in the heteroalkyl group.
  • Examples include: -0-CH 2 -CH 2 -CH 3 , -CH 2 -CH 2 CH 2 -OH, -C3 ⁇ 4- CH2-NH-CH3, -CH 2 -S-CH 2 -CH 3 , and -CH 2 CH 2 -S(0)-CH 3 .
  • Up to two heteroatoms may be consecutive, such as, for example, -CH 2 -NH-OC3 ⁇ 4, or -CH 2 -CH 2 -S-S-C3 ⁇ 4.
  • halo or halogen by themselves or as part of another substituent mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom, preferably, fluorine, chlorine, or bromine.
  • aromatic refers to a carbocycle or heterocycle having one or more polyunsaturated rings having aromatic character (4n+2) delocalized ⁇ (pi) electrons).
  • aryl employed alone or in combination with other terms, means, unless otherwise stated, a carbocyclic aromatic system containing one or more rings (typically one, two or three rings) wherein such rings may be attached together in a pendent manner, such as, for example, a biphenyl, or may be fused, such as, for example, naphthalene. Examples include phenyl; anthracyl; and naphthyl.
  • aryl-(Ci-C3)alkyl means a radical wherein a C1-C3 alkylene chain is attached to an aryl group, e.g., -CH 2 CH2-phenyl.
  • substituted aryl-(Ci-C3)alkyl means an aryl-(Ci-C3)alkyl radical in which the aryl group is substituted.
  • heterocycle or “heterocyclyl” or “heterocyclic” by itself or as part of another substitiient means, unless otherwise stated, an unsubstituted or substituted, stable, mono- or multicyclic heterocyclic ring system which consists of carbon atoms and at least one heteroatom selected from N, O, and S, and wherein the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen atom may be optionally quaternized.
  • the heterocyclic system may be attached, unless otherwise stated, at any heteroatom or carbon atom which affords a stable structure.
  • heteroaryl or “heteroaromatic” refers to a heterocycle having aromatic character.
  • a polycyclic heteroaryl may include one or more rings which are partially saturated. Examples include tetrahydroquinoline and 2,3-dmydrobenzofuryl.
  • non-aromatic heterocycles include monocyclic groups such as, for example: pyrrolidine, pyrroline, imidazoline, 2,3-dihydrofuran, 2,5-dihydrofi.iran, tetrahydrofuran, thiophane, piperidine, 1,2,3,6-tetrahydropyridine, 1,4-dihydropyridine, piperazine, morpholine, thiomorpholine, pyran, 2,3-dihydropyran, tetrahydropyran, 1,4- dioxane, 1,3-dioxane, homopiperazine, homopiperidine, 1,3-dioxepane, 4,7-dihydro-l,3- dioxepin and hexamethyleneoxide.
  • monocyclic groups such as, for example: pyrrolidine, pyrroline, imidazoline, 2,3-dihydrofuran, 2,5-dihydrofi.iran, t
  • heteroaryl groups mclude: Pyridyl, pyrazmyl, pyrimidinyl, particularly 2- and 4-pyrirmdinyl, pyridazinyl, thienyl, furyl, pyrrolyl, particularly 2- pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, particularly 3- and 5-pyrazolyl, isothiazolyl, 1,2,3-traizolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl.
  • polycyclic heterocycles include: Indolyl, particularly 3-, 4-, 5-, 6- and 7-indolyl, indolinyl, quinolyl, tetrahydroquinolyl, isoquinolyl, particularly 1- and 5- isoquinolyl, 1,2,3,4-tetrahydroisoquinolyl, cinnolinyl, quinoxalinyl, particularly 2- and 5- quinoxalinyl, quinazolinyl, phthalazinyl, 1,8-naphthyridinyl, 1,4-benzodioxanyl, coumarin, dihydrocoumarin, benzofuryl, particularly 3-, 4-, 1,5-naphthyridinyl, 5-, 6- and 7-benzofuryl, 2,3-dihydrobenzofiryl, 1,2-benzisoxazolyl, benzothienyl, particularly 3-, 4-, 5-, 6-and 7-benzothienyl, benzoxazolyl,
  • hydrocarbyl refers to any moiety comprising only hydrogen and carbon atoms.
  • Preferred hydrocarbyl groups are (Ci-Ci2)hydrocarbyl, e.g., (Ci-C7)hydro- carbyl such as, for example, benzyl and (Ci-Ce)alkyl.
  • substituted means that an atom or group of atoms has replaced hydrogen as the substituent attached to another group.
  • substituted refers to any level of substitution, namely mono-, di-, tri-, tetra-, or penta-substitution, where such substitution is permitted.
  • the substituents are independently selected, and substitution may be at any chemically accessible position.
  • the present invention provides a novel compound of the following formula:
  • X is a halogen atom
  • R 1 is -H, or -C1-C12 hydrocarbyl
  • R 2 and R 3 form, together with the oxygen atoms to which they are attached, a 5 to 10 membered heterocyclic ring, which heterocyclic ring is optionally substituted with 1, 2 or 3 substituents independently selected from a Ci straight-chain hydrocarbyl group, a C 3 . branched or cyclic hydrocarbyl group, and a carbocyclic ring A; wherein said carbocyclicring A is bonded to the 5 to 10 membered heterocyclic ring via:
  • carbocyclic ring A is optionally substituted by 1, 2 or three substituents independently selected from -Ci-Ce alkyl, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or t-butyl; -C6-C10 aryl, such as, for example, phenyl, tolyl or naphthyl and -Ce-Cio aryl-Ci-C3 alkyl, such as, for example, benzyl, 1-phenylethyl, 2- phenylethyl, or a or ⁇ naphthylmethyl.
  • -Ci-Ce alkyl such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or t-butyl
  • -C6-C10 aryl such as, for example, phenyl, tolyl or naph
  • R 2 and R 3 can together with the oxygen atoms to which they are attached form a below:
  • R 4 and R 5 are independently selected from -H, -Cj-6 alkyl, and -Ce-io aryl; or R 4 and R 5 together with the carbon atom to which they are attached form a 5 to 6 membered spiro-fused carbocyclic ring, which is optionally substituted by 1, 2 or three substituents independently selected from -Ci-Ce alkyl, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or t-butyl; -Ce-Cio aryl, such as, for example, phenyl, tolyl or naphthyl and -Ce-Cio aryl-Ci-C3 alkyl, such as, for example, benzyl, 1-phenylethyl, 2- phenylethyl, or a or ⁇ naphthylmethyl.
  • R 2 and R 3 together with the atoms to which they are attached, form an alkylidene ring, such as, for example, a methylidene or isopropylidene ring, or an alkoxymethylidene ring such as, for example, ethoxymethylidene; each optionally substituted with 1, 2 or 3 substituents independently selected from -Ci-Cg alkyl or -C6-C 3 aryl.
  • R 2 and R 3 together can form an alkylidene group such as a methylidene or isopropylidene group, or an alkoxymethylidene group such as, for example, ethoxymethylidene; each optionally substituted with 1, 2 or 3 substituents independently selected from -Ci-Cs alkyl or -Ce-Cg aryl.
  • a spiro fused system formed by R 4 and R 5 can be, for example:
  • the two oxygen atoms are understood to correspond to the two oxygen atoms to which the R 2 and R 3 substkuents are attached.
  • R 1 is -H, a -C1-C6 alkyl group, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or t-butyl; a -Ce-Cio aryl group, such as, for example, phenyl, alpha naphthyl or beta naphthyl; or a -Cs-Cioar HCi- C2)alkyl, such as, for example, benzyl, phenylethyl or naphthylmethyl.
  • a -C1-C6 alkyl group such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or t-butyl
  • a -Ce-Cio aryl group such as, for example, phenyl, alpha naphthyl or beta naphthyl
  • -C(O)OCH 2 (C 6 -C 10 )aryl such as -C(0)Obenzyl.
  • R 2 and R 3 are protecting groups
  • these groups can typically be added and removed using conventional protecting group methodology, for example, as described in "Protective Groups in Organic Chemistry,” edited by J W F McOmie, Plenum Press (1973), and “Protective Groups in Organic Synthesis", 2nd edition, T W Greene & P G M Wutz, Wiley-Interscience (1991).
  • the present invention provides the novel compounds, ethyl( 2-((3aR,4S,6R,6aS)-4-(6-cUoro-5-rn1ro-2-(propylmio)pyrimidin-4- ylamino)-tetrahydro-2,2-dimethyl-3aH-cyclopenta[d][l,3]dioxol-6-yloxy)acetate (Compound 7); ethyl (2-((lS,2S,3S,4R)-4-(6-cMoro-5-mtro-2-(propyltMo)pyrinudin-4-yl- ammo)-2,3-dihydroxycyclopentyloxy)acetate (Compound 7a); and ethyl 2- ((3aS,4R,6S,6aR)-4-(6-cMoro-5-mrro-2-(propyltMo)p
  • the present invention provides a novel compound 8 of the following formula:
  • X is a halogen atom
  • R 2 , and R 3 are defined as above.
  • the present invention provides the novel compounds, 2-( ⁇ 3aR, 4S, 6R, 6aS)-6- ⁇ [5-amino-6-cMoro-2-(propyltMo)-4-pyrimidinyl- amino ⁇ -2, 2-dhnethyltetrahydro-3aH-cyclopenta[d] [l,3]dioxol-4-yl)oxy]-l-acetic acid (Compound 8a); and 2-((3aR,4S,6R,6aS)-4-(5-amino-6-c oro-2-( ropyItluo)pyrinndin-4- ylammo)tetrahydro-3aH-spiro[cyclopenta[d][l,3]dioxole-2,l'-cyclopentane]-6- yloxy)acetic acid (Compound 8a'); shown in the structure diagrams below:
  • the present invention provides the novel compounds, 2-( ⁇ 3aR,4S,6R,6aS)-6-[7-chloro-5-(propyltbio)-3H-[l,2,3]triazolo[4,5- d]pyrimidin-3-yl]-2,2-dimemyltetrahydro-3aH-cyclopenta[d][l,3]dioxol-4-yl ⁇ oxy)-l- acetic acid (Compound 9a); and 2-((3aR,4S,6R, 6aS)-4-(7-chloro-5-(propylthio)-3H- [l,2,3]Mazolo[4,5-d]pyrirmdin-3-yl)tetr ⁇
  • the present invention provides an isolated compound and its salts, having the following formula:
  • R 1 , R 2 and R 3 are as defined as above.
  • the present invention provides isolated compounds ethyl 2-((3aR,4S,6R,6aS)-6-ammo-2,2-dimethyltetrahydro-3aH-cyclo- penta[d][l,3]dioxol-4-yloxy)acetate and ethyl 2 (3aR,4S,6R,6aS) ⁇ -aminotetrahydro- 3aH-spiro[cyclopenta[d][l,3]dioxole-2,l'-cyclopentane]-6-yloxy)acetate having the following two formulae:
  • e invention provides a novel compounds, having the follo
  • R 1 is as
  • the present invention provides the novel compounds, emyl (2-((lS,2S,3S,4R)-4-(7 Moro-5-( ropylthio)-3H-[l,2,3]triazolo[4,5- d]pyrimidin-3-yl)-2,3-dihydroxycyclopentyloxy)acetate (Compound 9b); and ethyl 2-
  • the present invention provides a novel compounds, having the fo
  • R 1 is defined as above.
  • the present invention provides the novel compounds, ethyl[3aR-[3aa,4a,6a(lR*,2S*),6aa]]-[[6-[7-[[2-(3,4-difluorophenyl)cyclo- propyl]ammo]-5-( ropylttoo)-3H-l,2,3-lria
  • the present invention encompasses a process for preparing Ticagrelor by preparing any one of the above mentioned compounds and further converting it to Ticagrelor, for example according to the process described below.
  • the present invention provides improved processes for preparing Ticagrelor, according to the following Schemes.
  • Ticagrelor can be obtained by a process as shown in Schemes 2 and 2a above.
  • the process is high yielding and several core intermediates, e.g., intermediates 8a, 9a and 10a are solid materials that are readily purified on commercially useful scales.
  • the invention provides novel compounds of Formula 8 a':
  • R 1 is as described above;
  • X is a leaving group that can be removed or substituted by conventional methods; and
  • R 2 and R 3 are as defined above.
  • the leaving group X is selected, for example, from halogens, such as, for example, -CI, -Br and -I.
  • the invention also provides compounds according to Formulae 9a and 9a':
  • the present invention provides the novel compounds, ethyl 2-((3aR,4S,6R,6aS)-6-(5-ammo-6-cMoro-2-(propylt o)pyrmiidm-4- ylamino)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][l,3]dioxol-4-yloxy)acetate:
  • the invention provides a process of preparing Ticagrelor, said process comprising coupling the compound according to Formula 5 :
  • X is a leaving group, for example, 4,6-dicliloro-2-(propylthio)pyrimidin-5- amine, to form a compound of Formula 8a, as described above; wherein R 1 is as described above; and X is a leaving group;
  • ester compound 1 la ethyl 2- ((lS s 2S,3S,4R)-4-(7 (lR,2S)-2 3,4-difluorophenyl)cyclopropylammo)-5-(propylthio)- 3H-[l,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,3-dihydroxycyclopentyloxy)acetate:
  • the step of hydrolyzing a Formula XVb ester compound to a Formula 8a acid compound may be carried out using a suitable base, and is preferably carried out in a suitable solvent.
  • Suitable base can be alkali metal hydroxide or carbonates or bicarbonates
  • Suitable solvents include polar solvents, such as, for example Ci-Ce alcohols, e.g., methanol, ethanol, propanol and isopropanol, acetonitrile, tetrahydrofuran, NMP, mixtures of these solvents, and mixtures thereof with water.
  • the step of diazotizing the Formula 8a acid can be carried out, for example, by reacting the Formula 8a acid with a suitable diazotizing agent, preferably, in the presence of a suitable solvent.
  • suitable diazotizing agents include, for example sodium nitrite and isoamyl nitrite.
  • Suitable solvents for carrying out this reaction include polar organic solvents such as, for example, methanol, ethanol, or acetonitrile, mixtures thereof, and mixtures thereof with water and water alone.
  • the step of coupling the Formula 9a with (lR,2S)-2-(3,4-difluorophenyl)cyclo- propanamine can be carried out, for example, by reacting the two compounds in the presence of a suitable base, preferably in the presence of a suitable solvent.
  • suitable bases include organic bases, such as triethyl amine and diisopropyl ethyl amine and inorganic bases, such as, for example sodium bicarbonate, sodium carbonate, potassium bicarbonate and potassium carbonate.
  • Suitable solvents include solvents that are inert to the reaction conditions and in which the reagents are soluble.
  • the reaction can be carried out in a single phase in solvents including halogenated solvents such as, for example, dichloromethane or dichloroethane, ethers such as t-butylmethyl ether or THF, and other suitably inert organic solvents.
  • halogenated solvents such as, for example, dichloromethane or dichloroethane
  • ethers such as t-butylmethyl ether or THF
  • other suitably inert organic solvents e.g., a two-phase reaction, i.e., with water and a suitable organic solvent such as toluene or THF.
  • dimethyltetrahydro-3aH-cyclopenta[d][l,3]dioxol-4-yloxy)acetic acid (10a) to Ticagrelor can be carried out by a reaction with a suitable reducing agent.
  • suitable reducing agents include hydride reagents, for example LAH, NaBH 4 -BF 3 .OEt 2 or Redal; diborane or SmL, followed by deprotecting the acetonide in acidic conditions.
  • 10a is deprotected in acidic conditions to give the compoimd 11a, followed by the reduction of acid group using suitable reducing agents include, hydride reagents, for example LAH, NaBH 4 -BF 3 .OEt 2 or Redal; diborane or Sml 2 .
  • suitable reducing agents include, hydride reagents, for example LAH, NaBH 4 -BF 3 .OEt 2 or Redal; diborane or Sml 2 .
  • the present invention also provides the following process for preparation Ticagrelor, represented by two following reaction schemes 5a, 5b and 6:
  • Ticagrelor can be obtained by a process as shown in the above Schemes 5 A, 5B and 6; wherein R 1 is as described above
  • intermediates III/IIIa, IV/IVa, V/Va, IX/IXa, X/Xa, and XII XIIa are solid materials that are readily purified on commercially useful scales.
  • One significant advantage of the above process is observed in the coupling of intermediates Vl/VIa and IX/IXa to form intermediate X/Xa. In the above process, this step produces no dimer byproduct (resulting from couplmg of both aromatic chloro groups). This reaction can be accomplished in as little as 2-3 hrs.
  • the above process carries out the final coupling with (lR)-2-(3,4- chfluorophenyl)cyclopropanamine on the unprotected diol intermediate XII/XIIa.
  • This synthesis step is thus not subject to the significant amounts of isomerization of the cyclopropyl amine optical center that is a known problem associated with some other synthesis routes.
  • this process does not require any column chromatographic purification steps.
  • the invention provides novel compounds of formula (IX):
  • X is a leaving group that can be removed or substituted by conventional methods.
  • the leaving group X is selected, for example, from halogens, such as, for example, -CI, -Br and -I.
  • R a is -H and R b is an amino protecting group.
  • the amino protecting group may be selected from, for example, carboaryloxy (benzyloxy), p- alkoxybenzyloxy carbonyl , tert-butyloxycarbonyl , 9-fluorenylmethylcarbonyl, alkanoyl, such as, for example, Ci-Ce alkanoyl, benzoyl, a carbamate group, and sulfonamide groups.
  • the amino protecting group is selected from -C(0)OCi-C6 alkyl, such as, for example, carboethoxy, carbomethoxy and t-butoxy- carbonyl; optionally substituted - (0) aryl, such as, for example, benzyloxy- carbonyl and p-methoxybenzyloxycarbonyl; optionally substituted aryl(Ci- C3)alk L such as, for example, benzyl, phenethyl, p-methoxybenzyl, 2,3-dimethoxy- benzyl, 2,4-dimethoxybenzyl and 9-fluorenylmethyl; optionally substituted -C7 arylcarbonyl, such as, for example, benzoyl; -Ci-Q alkanoyl, such as, for example, formyl, acetyl, and propionyl; -C Ce alkylsulfonyl, such as, for example, mesyl
  • phenylsulfonyl such as, for example, benzenesulfonyl, toluenesulfonyl (tosyl) and 3-nitrobenzenesulfonyl; -Si(Ci-C6 alkyl such as, for example, iert-butyldimetliylsilyl; -C1-C6 alkylcarbamoyl, such as, for example, dimethylcarbamoyl; and optionally substituted -C7-C10 arylalkyl carbamoyl, such as, for example, benzyl carbamoyl.
  • phenylsulfonyl such as, for example, benzenesulfonyl, toluenesulfonyl (tosyl) and 3-nitrobenzenesulfonyl
  • -Si(Ci-C6 alkyl such as, for example, iert-butyldimetl
  • suitable amino protecting groups include tosyl, formyl, p- methoxybenzyl, acetyl, 3,4-dimethoxybenzyl, and p-methoxyphenyl.
  • benzyloxycarbonyl examples include benzyloxycarbonyl, benzyl, 2,4-dimethoxybenzyl, mesyl, tert-butyloxycarbonyl , 9-fluorenylmethyl, carboethoxy, and carbomethoxy.
  • R a is -H
  • R b is an amino protecting group as defined above.
  • R a is -H
  • R b is -C(0)H, acetyl, propionyl, benzoyl, carbobenzyloxy, carbomethoxy, carboethoxy, or t-Boc.
  • R° is a -C1-C6 alkyl group. According to some embodiments R° is methyl, ethyl, propyl or isopropyl. According to some embodiments R c is propyl.
  • the present invention provides the novel compound, N-(4,6-dicUoro-2-(propylt o)p rirmdui-5-yl)formamide, having the following structure;
  • the present invention provides novel compounds of formula (X):
  • R 2 and R 3 have also been defined supra.
  • R 2 and R 3 form, together with the oxygen atoms to which they are attached, a hetero below:
  • R 2 and R 3 together can form an alkylidene group such as a metbylidene or isopropylidene group, or an alkoxymethylidene group such as, for example, ethoxymethylidene; each optionally substituted with 1, 2 or 3 substituents independently selected from -CrCg alkyl or -C6-Cs aryl.
  • R 2 and R 3 can, together with the oxygen atoms to which they are attached, form a hetero below:
  • R 4 and R 5 are independently selected from -H, -Ci-6 alkyl, and -Ce-w aryl; or R 4 and R 5 together with the carbon atom to which they are attached form a 5 to 6 membered spiro-fused carbocyclic ring, which is optionally substituted by 1, 2 or three substituents independently selected from -C1-C6 alkyl, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or t-butyl; -Ci-Cio aryl, such as, for example, phenyl, tolyl or naphthyl and -Cg-Cio aryl-Ci-C3 alkyl, such as, for example, benzyl, 1-phenylethyl, 2- phenylethyl, or a or ⁇ naphthylmethyl.
  • R 1 is -H, a -Ci-Ce alkyl group, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or t-butyl; a -Ce-Cio aryl group, such as, for example, phenyl, alpha naphthyl or beta naphthyl; or a -C6-Cioaryl-(Ci- C2)alkyl, such as, for example, benzyl, phenylethyl or naphthylmethyl.
  • one or both of R 2 and R 3 are protecting groups selected from -Si(C,.
  • -C(0)OCH 2 (C 6 -Cio)aryl such as -C(0)Obenzyl.
  • the spiro system can be, for example:
  • the two oxygen atoms are understood to correspond to the two oxygen atoms to which the R 2 and R 3 substituents are attached.
  • the present invention provides a novel compound, N-(4- cmoro-6-(((3aS,4R,6S,6aR)-6-(2-hydroxyethoxy)-2,2-dmiemyl tetrahydro-3aH-cyclo- penta[d][l,3]dioxol-4-yl)amino)-2-(propylthio) pyrirnidin-5-yl) formamide, having the following structure:
  • the present invention provides novel compounds of Formula XI wherein X is as defined above; such as, for example, (lS,2S,3R,5S)-3-((5-ammo-6-chloro-2-(propylthio)- pyrimidm-4-yl)amino)-5-(2-hydroxyethoxy)cyclopentane-l,2-diol; as shown below:
  • the present invention provides a novel compound, (1S,2S,3R, 5S)-3-(7-chloro-5-(propylsulfanyl-triazolo) [4,5-d]pyrimidin-3-yl) -5 -(2- hydroxyethoxy)cyclopentane-l,2-diol (XII-A) Via (lS,2S,3S,5R)-3-(2-hydroxyethoxy)-5- (5-aimno-6-c oro-2-( ropy iio)pyrirnidin-4-ylamino) cyclopentane-l,2-diol, having the following structure:
  • the invention provides a process of preparing process of preparing a compound according to Formula I:
  • R c is a -Ci-Cs allcyl group, said process comprising coupling a compound according to Formula VI:
  • the invention thus provides a process of preparing Ticagrelor, said process comprising said process comprising coupling a compound of Formula VI:
  • the invention provides a process of preparing Ticagrelor, said process comprising coupling the compound 2-((3aR,4S,6R,6aS)-6-amino- 2,2-dimethyltetrahydro-3aH-cyclopenta[d][l,3]dioxol-4-yloxy)ethanol (Formula VI-A):
  • the step of coupling a Formula VI compound with a Formula ⁇ (or formula IX 1 ) compound can be carried out, for example, by reacting the compounds, preferably, in the presence of base and in a suitable solvent.
  • Suitable bases include organic bases such as, for example, triethyl amine, and diisopropylemylamine, and also inorganic bases, such as, for example, sodium bicarbonate and potassium bicarbonate.
  • Suitable solvents include any solvent in which the reactants dissolve and are stable.
  • Preferred solvents include polar organic solvents such as Ci-Ce alcohols such as methanol, ethanol and propanol, ethers such as t- butylmethyl ether and tetrahydrofuran, glycol solvents such as propylene glycol, polar aprotic solvents such as dimethylformamide and N-methylpyrrolidinone, mixtures of these solvents and mixtures thereof with water.
  • polar organic solvents such as Ci-Ce alcohols such as methanol, ethanol and propanol
  • ethers such as t- butylmethyl ether and tetrahydrofuran
  • glycol solvents such as propylene glycol
  • polar aprotic solvents such as dimethylformamide and N-methylpyrrolidinone
  • the conversion of a compound of Formula X to a compound of Formula I, or of, a compound of Formula X a or Formula X-A to Ticagrelor can comprise: removing the N- protecting group represented by R a and R b , and in some embodiments by only R b ;
  • the step of removing the N-protecting group can be carried out, for example, by hydrolysis.
  • the hydrolysis reaction may be carried out using a suitable acid reagent and is preferably carried out in a suitable solvent.
  • Suitable acid reagents include, for example mineral acids, such as hydrochloric acid, sulfuric acid and methanesulfonic acid, and organic acids such as trifluoroacetic acid.
  • Suitable solvents include polar solvents, such as, for example Ci-Cs alcohols, e.g. , methanol, ethanol, propanol and isopropanol, aceto- nitrile, tetrahydrofuran, dioxane, mixtures of these solvents, and mixtures thereof with water.
  • the O-protect groups R 2 and R 3 may be removed under the same conditions and in the same reaction step as is employed to remove the N-protecting group.
  • the step of diazotizmg the intermediate of Formula XI or XI- A to produce the intermediate of Formula XII (or Xlla) can be carried out, for example, by reacting the Formula XI or XIa compound with a suitable diazotizing agent, preferably, in the presence of a suitable solvent.
  • suitable diazotizing agents include, for example sodium nitrite and isoamyl nitrite.
  • Suitable solvents for carrying out this reaction include polar organic solvents such as, for example, methanol, ethanol, or acetonitrile, mixtures thereof, and mixtures thereof with water.
  • the diazotization reaction can be carried out directly on the hydrolysis reaction mixture used to remove the N- protecting group to prepare the Formula XI (or XIa) compound.
  • the step of coupling the Formula XII (or Xlla) triazolopyrimidine compound with the compound of Formula XIII ((lR,2S)-2-(3,4-difluorophenyl)cyclopropanamine) can be carried out, for example, by reacting the two compounds in the presence of a suitable base, preferably in the presence of a suitable solvent.
  • suitable bases include organic bases, such as triethyl amine and diisopropyl ethyl amine and inorganic bases, such as, for example sodium bicarbonate, sodium carbonate, potassium bicarbonate and potassium carbonate.
  • Suitable solvents include solvents that are inert to the reaction conditions and in which the reagents are soluble.
  • the reaction can be carried out in a single phase in solvents including halogenated solvents such as, for example, dichloromethane or dichloroethane, ethers such as t-butylmethyl ether or TUF, and other suitably inert organic solvents.
  • halogenated solvents such as, for example, dichloromethane or dichloroethane
  • ethers such as t-butylmethyl ether or TUF
  • other suitably inert organic solvents e.g., a two-phase reaction, i.e., with water and a suitable organic solvent such as toluene or THF.
  • the invention also provides an alternative process for preparation of Ticagrelor according to the two schemes below:
  • R a , R b , R c , R z , R 3 and X are as defined above; and R 1 is selected from -H, Ci-C 6 straight or branched alkyl, Ce-Cio aryl, and C7-C12 arylalkyl.
  • R c is n-propyl.
  • the invention provides a novel compound, 2-(((3aR,4S,6R, 6aS)-6-((6-chloro-5-form- amido-2-( ropyltmo)pyrirmdm-4-yl)am
  • the invention provides a process of preparing process of preparing a compound according to Formula I:
  • R c is a -Ci- alkyl group
  • the invention thus provides a process of preparing Ticagrelor when R c is n-propyl, said process comprising coupling a compound according to Formula V(a):
  • Formula XTV' compound (Formula XIV; R° is n-propyl) to Ticagrelor.
  • the invention provides a process of preparing Ticagrelor, the process comprising coupling the compound, 2-((3aR,4S,6R,6aS)-6-amino- 2,2-dimethyltetrahydro-3aH-cyclop l-4-yloxy)acetic acid:
  • the step of coupling a Formula V(a) compound with a Formula EX (or formula rX-b) compound can be carried out, for example, by reacting the compounds, preferably, in the presence of base and in a suitable solvent.
  • Suitable bases include organic bases such as, for example, triethyl amine, and diisopropylemylarnine, and also inorganic bases, such as, for example, sodium bicarbonate and potassium bicarbonate.
  • Suitable solvents include any solvent in which the reactants dissolve and are stable.
  • Preferred solvents include polar organic solvents such as Ci-Ce alcohols such as methanol, ethanol and propanol, ethers such as t- butylmethyl ether and tetrahydrofuran, glycol solvents such as propylene glycol, polar aprotic solvents such as dimethylfonnamide and N-methylpyrrolidinone, mixtures of these solvents and mixtures thereof with water.
  • polar organic solvents such as Ci-Ce alcohols such as methanol, ethanol and propanol
  • ethers such as t- butylmethyl ether and tetrahydrofuran
  • glycol solvents such as propylene glycol
  • polar aprotic solvents such as dimethylfonnamide and N-methylpyrrolidinone
  • the conversion of a compound of Formula XIV to a compound of Formula I, or of, a compound of XTV-A to Ticagrelor can comprise: removing the N-protecting group represented by R a and R b , and in some embodiments by only R b ; removing the O- protecting groups R 2 and R 3 ; diazotizing the intermediate of Formula XV or XVa to produce the intermediate of Formula XVI (or XVI-A) having the [1 ,2,3]triazolo[4,5- d]pyrirnidine ring system; coupling the triazolopyrimidine compound of Formula XVI (or XVI-A) with (lR)-2-(3,4-difluorophenyl)cyclopropananiine (Formula ⁇ ):
  • the step of removing the N-protecting group can be carried out, for example, by hydrolysis.
  • the hydrolysis reaction may be carried out using a suitable acid reagent and is preferably carried out in a suitable solvent.
  • Suitable acid reagents include, for example mineral acids, such as hydrochloric acid, sulfuric acid and organic acids such as metliaiiesiilfonic acid, and trifmoroacetic acid.
  • Suitable solvents include polar solvents, such as, for example Cj-C6 alcohols, e.g., metlianol, ethanol, propanol and isopropanol and other organic solvents such as acetonitrile, tetraliydiOfuran, mixtures of these solvents, and mixtures thereof with water.
  • the O-protect groups R 2 and R 3 may be removed under the same conditions and in the same reaction step as is employed to remove the N-protecting group.
  • the step of diazotizing the intermediate of Formula XV or XV-A to produce the intermediate of Formula XVI (or XVI- A) can be carried out, for example, by reacting the Formula XV or XV-A compound with a suitable diazotizing agent, preferably, in the presence of a suitable solvent.
  • suitable diazotizing agents include, for example sodium nitrite and isoamyl nitrite.
  • Suitable solvents for carrying out this reaction include polar organic solvents such as, for example, methanol, ethanol, or acetonitrile, mixtures thereof, and mixtures thereof with water.
  • the diazotization reaction can be carried out directly on the hydrolysis reaction mixture that was used to remove the N-protecting group to prepare die Formula XV (or XV-A) compound.
  • the step of coupling the Formula XVI (or XVI- A) triazolopyrimidine compound with the compound of Formula XIII ((lR)-2-(3,4-o3 ⁇ 4fluorophenyl)cyclopropanarnine) can be carried out, for example, by reacting the two compounds in the presence of a suitable base, preferably in the presence of a suitable solvent.
  • suitable bases include organic bases, such as triethyl amine and diisopropyl ethyl amine and inorganic bases, such as, for example sodium bicarbonate, sodium carbonate, potassium bicarbonate and potassium carbonate.
  • Suitable solvents include solvents that are inert to the reaction conditions and in which the reagents are soluble.
  • the reaction can be carried out in a single phase in solvents including halogenated solvents such as, for example, dichloromethane or dichloroethane, ethers such as t-butylmethyl ether or THF, and other suitably inert organic solvents.
  • halogenated solvents such as, for example, dichloromethane or dichloroethane
  • ethers such as t-butylmethyl ether or THF
  • other suitably inert organic solvents e.g., a two-phase reaction, i.e., with water and a suitable organic solvent such as toluene or THF.
  • the conversion of a compound of Formula XVII, or Formula XVII- A to Ticagrelor requires a functional group transformation of the carboxylic ester to a primary alcohol.
  • This transformation can be accomplished, for example by reduction of the ester using a suitable reducing agent.
  • suitable reducing agents are those that can selectively reduce the ester moiety, for example hydride reagents, such as sodium borohydride- BF3.0Et2, lithium borohydride, lithium triethylborohydride, LAH, L-selctride and diboraiie and its complexes
  • the reaction is preferably done in the presence of a suitable solvent, for example, THF or dioxane.
  • Example 3a Preparation of ethyl 2-((3aR,4S,6R,6aS)-6-(benzyloxycarbonylamino)-2,2- dimethyltetrahydro-3aH-cyclopenta[d][l,3]dioxol-4-yloxy)acetate (compound 4(1)
  • Example 4a Preparation of ethyl 2-((3aR,4S,6R,6aS)-6-(tert-butoxycarbonylamino)-2,2- drmethyltetrahydro-3aH-cyclopenta[d][l,3]dioxol-4-yloxy)acetate (compound 4).
  • Example 5a Preparation of ethyl 2-((3aR,4S,6R,6aS)-6-arnmo-2,2-dimethyltetrahydro- 3aH-cyclopenta[d][l,3]dioxol-4-yloxy)acetate
  • reaction mixture was then quenched with water (500 mL) and extracted with DCM (2 x 3 V). The DCM layer was distilled off. The thus obtained residue was suspended in ethanol (5V) and oxalic acid (13.68g) was added. This reaction mixture was heated to
  • Example 7a Preparation of ethyl 2-((3aR,4S,6R,6aS)-6-(6-cUoro-5-nitro-2-(propylthio)- pyrinn ⁇ in-4-ylammo)-2,2-dimethyltetrahydro-3 aH-cyclopenta[d] [1,3] dioxol-4-yloxy)- acetate (compound 7)
  • Example 8 Preparation of ethyl 2-((3aR,4S,6R,6aS)-6-(5-ammo-6-chloro-2-(propylthio)- pyrirmdm-4-ylamno)-2,2-dimethyltetrahy
  • Example 8a Preparation of ethyl 2-((3aR,4S,6R,6aS)-6-(5-amino-6-chloro-2- ( ropyltHo)pyrimidm-4-ylaimno)-2 ⁇
  • Iron powder (8.53g) was added to a solution of compound 7 (25 g) in methanol (5V) and acetic acid (76.37 mL). The reaction mixture was then stirred at 35° C for 2 hrs. The reaction was monitored by TLC. After the reaction was complete, the product was extracted with ethyl acetate. The extract was concentrated under reduced pressure to give compound 8 (8.0g), which was used for the next step without further purification.
  • Example 9a Preparation of ethyl 2-((3aR,4S,6R,6aS)-6-(7-chloro-5-(propylthio)-3H- [1,2,3 ]triazole[4,5-d]pyrirmdm-3-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][l,3]- dioxol-4-yloxy)acetate (compound 9) To a solution of compound 8 (20 g) in acetonitrile (10V) was added isoamylnitrite (7.77g). The reaction mixture was heated to 40°C for 2 hours. Then the reaction mixture was cooled to room temperature and concentrated at reduced pressure to give compound 9 (19.5g). The crude product was used for next step without further purification.
  • Example 10a Preparation of ethyl 2-((3aS,4R,6S,6aR)-4-(7-((lR,2S)-2-(3,4-difluoro- phenyl)cyclopropylammo)-5-(propyItido)-3H-[l,2,3]tri
  • Example 11a Preparation of 2-((3aS,4R,6S,6a )-4-(7-((lR,2S)-2-(3,4-difluorophenyl)- cyclopropylarrmo)-5-(propylthio)-3H- ⁇
  • reaction was monitored by TLC. After completion, the reaction was quenched with water (50 mL), and the THF was distilled off under reduced pressure to provide a residue.
  • Iron powder (15.62 g) was added to a solution of compound(16) in methanol (10 vol) and acetic acid (5.0 vol) at RT. The resulting reaction mixture was stirred for 3-5 hrs at 50°C. The reaction was monitored by TLC. The product was extracted by adding water (5.0vol). The resulting mixture was filtered and the filtrate was distilled off under reduced pressure at 40-50°C to form a residue. The obtained residue was extracted with ethyl acetate (500-600ml). The ethyl acetate extract was washed with aqueous sodium bicarbonate and then concentrated under reduced pressure. The thus obtained residue was crystallized. Isolated yield 90-95%.
  • the combined filtrate was concentrated do dryness under reduced pressure at 40-50 °C.
  • Example 17a Preparation of ethyl 2-((3aR,4S,6R,6aS)-6-(5-amino-6-chloro-2- (propyltMo)pyrimidin-4-ylamino)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][l,3]dioxol- 4-yloxy)acetate
  • Example 19a 2-((3aR,4S,6R,6aS)-6-(7-chloro-5-(propylthio)-3H-[l ,2,3]triazolo[4,5- d]pyrimidm-3-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][l,3] hoxol-4-yloxy)aceti ⁇ acid (compound 9a)
  • Example 21a Preparation of 2-((3aR,4S,6R,6aS)-6-(7-((lR,2S)-2-(3,4-difluorophenyl)- cyclopropylamino)-5-( ropyltMo)-3H-[l,2,3]M
  • Example 24a Preparation of ethyl 2-((lS,2S,3S,4R)-4-(7-chloro-5-(propylthio)-3H- [l,2,3]1riazole[4,5-d]pyrimidm-3-yl)-2,3-dmydroxycyclopentyloxy)acetate (compound 9b)
  • compound 9b To a solution of compound 8b (4.5 g) in acetonitrile (lOvol) was added isoamylnitrite (1.87g) at 30°C. The reaction mixture was stirred at 60-65°C for 3-5h. The reaction was monitored by TLC.
  • Example 25 Preparation of ethyl 2-((lS,2S,3S,4R)-4-(7-((lR,2S)-2-(3,4-difluorophenyl)- cyclopropylamino)-5-(propyltWo)-3H-[l,2,3]triazolo[4,5-d]pyriniidin-3-yl)-2,3- dihydroxycyclopentyloxy)acetate (compound 11a)
  • Example 25a Preparation of ethyl 2-((lS ⁇ S,3S,4R)-4-(7-((lR,2S)-2- ⁇ 3,4-difluoro- phenyl)cyclopropylmmno)-5-(propyltlno)-3H-[l,2,3]triazolo[4,5-d]pyrimidm-3-yl)-2,3- dihydroxycyclopentyloxy)acetate (compound 11a)
  • Example 26 Preparation of methyl 2-((lS,2S,3S,4R)-4-(7-((lR,2S)-2-(3,4-difluoro- phenyl)cyclopropylammo)-5-( ropyltMo)-3H-[l,2,3]triazolo[4,5-d]pyrimidm-3-yl)- ⁇
  • Example 30 Preparation of ethyl 2-((3aS,4R,6S,6aR)-4-(benzyloxycarbonylamino)- te1rahy03 ⁇ 4o-3aH-spiro[cyclopenta[d][l,3]dioxole-2,r-cyclopentane]-6-yloxy)acetate
  • Example 31 Preparation of ethyl 2-((3aS,4R,6S,6aR)-4-(tert-butoxycarbonylamino)tetra- hydro-3aH-spiro[cyclopenta[d][l,3]dioxole-2,r-oyclopentane]-6-yloxy)acetate
  • Example 37 Preparation of 2-((3aS,4R,6S,6aR)-4-(7-cMoro-5-(propyltliio)-3H- [1 ,2,3]triazole[4,5-d]pyrirmdin-3-yl)tetrahydro-3aH-spiro[cyclopenta[d][l ,3]dioxole-2 , 1 '- cyclopentane]-6-yloxy)ethanol
  • Example 38 Preparation of 2-((3aS,4R,6S,6aR)-4-(7-((lR,2S)-2-(3,4-difiuorophenyI)- cyclopropylarmno)-5-( ropylthio)-3H-[l,2 ]triazolo[4,5-d]pyrimidm-3-yl)tetrahydro- 3aH-spiro[cyclopenta[d][l,3]dioxole-2, -cyclopentane]-6-yloxy)ethanol
  • Iron powder (15.62 g) was added to a solution of compound 6 in methanol (10 vol) and acetic acid (5.0 vol) at ⁇ 30°C, and the resulting reaction mixture was stirred for 3-5hrs at 50°C. The reaction was monitored by TLC. The reaction mixture was worked up by adding water (5.0 vol) and filtering. The filtrate was concentrated under reduced pressure at 40-50°C to produce a residue. The residue was extracted with ethyl acetate (500- 600ml) and the combined ethyl acetate fraction was washed with aqueous sodium bicarbonate and concentrated under reduced pressure. The thus obtained residue was crystallized from n-hexane. Isolated yield 90-95%.
  • Example 41a Preparation of benzyl (lR,2S,3S,4S)-2,3-dihydroxy-4-(2-hydroxyethoxy)- cyclopentylcarbamate
  • Example 42a Preparation of benzyl (3aR,4S,6R,6aS)-4-(2-hydroxyethoxy)tetrahydro- 3 aH-spiro [cyclopenta[d] [ 1 ,3]dioxole-2, 1 -cyclopentane] -6-ylcarbamate
  • Example 45 Preparation of benzyl (3aR,4S,6R,6aS)-tetrahydro-4-hydroxy-2,2- dimethyl-3aH-cyclopenta[d] [1 ,3]dioxol-6-ylcarbamate
  • Compound II 50 g, 0.288 mol
  • MIBK 900 mL
  • Water (250 mL) and potassium carbonate 47.80 g, 0.346 mol
  • the reaction mixture was stirred at the same temperature for 30-min, and men added solution of benzyl chloroformate 50% in Toluene ( 54.16 g, 0.317 mol) was added slowly over 30 min at 25- 30°C.
  • reaction mixture was stirred at 25-30°C for 6h. Reaction progress was monitored by TLC. When the reaction was complete, the aqueous and organic layers were separated, and the aqueous layer was extracted with MIBK (250 mL). The combined organic fraction was dried over anhydrous Na 2 S04 and concentrated under reduced pressure at 40-50°C to provide a residue. The residue was mixed with n-hexane (500 mL) and stirred at 25-30°C for lh. A precipitate foimed and the solid was isolated by filtration and washed with n-hexane (100 mL). The collected compound 3(1) was dried under vacuum at 40°C over 12h, isolated.
  • Example 46 Preparation of ethyl 2-(((3aR,4S,6R,6aS)-6-(((benzyloxy)carbonyl)amino)- 2,2-dimethyltetraliydro-3aH-cyclopenta[d][l,3]dioxol-4yl)oxy)acetate
  • Example 48 Preparation of 2-(((3aR,4S,6R,6aS)-6-(((benzyloxy)carbonyl)amino)-2,2- dimethyl tetrahydro -3aH-cyclopenta[d][l,3]dioxol-4-yl)oxy)acetic acid (IV-a), via ethyl 2-(((3a R,4 S,6 R,6a.5)-6-(((benzyloxy)carbonyl)amino)-2,2-dimemyltetrahydro -3a ii-cyclopenta[ ⁇ fl[l,3]dioxol-4-yl)oxy)acetate (IV)
  • a suspension of sodium hydride 60% (3.9 g) in DMF (2-10V) is cooled to -50 to 0°C.
  • Compound ⁇ (20 g,) is dissolved in DMF (2-10V) and added to the reaction flask over 10 to 30 min.
  • the reaction mixture is stirred at the same temperature for 10 to 30 min.
  • a solution of ethylbromoacetate (13.04 g) in DMF (80 mL) is added dropwise.
  • the reaction mixture is stirred at the same temperature for l-2hrs.
  • the reaction progress is monitored by TLC.
  • the reaction is quenched by addition of acetic acid and water (600 mL).
  • the aqueous layer is extracted with ethyl acetate (400 mL).
  • the organic layer is concentrated to dryness.
  • the obtained residue is dissolved in THF (60 mL) and charged into a reaction flask.
  • the reaction flask is cooled to below 10°C and a solution of NaOH (7.8 g) in water (30 mL) is added.
  • the reaction mixture is stirred at RT for 2-6hrs.
  • the THF layer is distilled off and the aqueous layer is washed with ethyl acetate (80 mL).
  • the aqueous layer is acidified to pH 2-3 and extracted with ethyl acetate (3 x 100 mL).
  • the combined organic layer is dried over anhydrous sodium sulphate and concentrated to dryness to give compound IV-a.
  • Example 48a Preparation of 2-(((3aR,4S,6R,6aS)-6-(((benzyloxy)carbonyl)amino)-2,2- dimethyl tetrahydro -3aH-cyclopenta[d][l,3]dioxol-4-yl)oxy)acetic acid (IV-a), via ethyl 2-(((3a R,4 S,6 R,6n 5)-6-(( ⁇ enzyloxy)carbonyl)ammo)-2,2-drmethyltetrahydro -3a #-cyclopenta[ d ⁇ [ 1 ,3]dioxol-4-yl)oxy)acetate (TV)
  • Example 49 Preparation of 2-(((3aR,4S,6R,6aS)-6-(((berizyloxy)carbonyl)amino)-2,2- dimethyltetrahydiO-3aH-cyclopenta[d]fl,3]dioxol-4-yl)oxy)acetic acid (IV-a) - via ethyl 2-(((3aR,4S,6R,6a. 3 ⁇ 4-6-(((herizyloxy)carbonyl)ammo)-2,2-dimethyltetrahydro-3a -cyclopenta [l,3]dioxol-4-yr)oxy)acetate (IV).
  • Example 49a Preparation of 2-(((3aR,4S,6R,6aS)-6-(((benzyloxy)carbonyl)amino)-2,2- dimethyltetra hydro -3aH-cyclopenta [d][l,3]dioxol-4-yl)oxy)acetic acid (IV-a) - via ethyl 2-(((3a R,4 5,6 i?,6a 5)-6-(((benzyloxy)carbonyl)ainino)-2,2-dimethyltetraliydro - 3a ⁇ -cyclopentaf d][l,3]dioxol-4-yl)oxy)acetate (IV).
  • Example 50a Preparation of 2-((3aS,4R,6S,6aR)-4-amino-tetrahydro-2,2-dimethyl-3aH- cyclopenta[d][l,3]dioxol-6-yloxy)acetic acid:
  • Iron powder (15.62 g) was added portionwise to a solution of compound VII (25g) in methanol (5V) and acetic acid (3V) at ⁇ 30°C. The resulting reaction mixture was stirred for 3-5hrs at 35°C. The reaction mixture was then passed through a diatomaceous earth (Celite) pad. Water (400 mL) was added and the mixture was extracted with toluene (3 x 150 mL). The combined organic layer was washed with water (2 x 150 mL). The toluene layer was concentrated to half volume and added into a rb flask containing formic acid (51.5 mL). This mixture was cooled 0-5°C and acetic anhydride (57.11 g) was added dropwise.
  • Example 52 Preparation of 2-(((3a R,A S,6 R,6a S)-6-((6-chloro-5-formamido-2- (propylthio) pyriimdm-4-yl)arruno)-2,2-dimethyltetrahydro-3a /f-cyclopenta[ rf][l,3]dioxol-4-yl)oxy)acetic acid:
  • Example 53 methyl 2-(((l 5,25,3 5,4 ⁇ )-4-(7-chloro-5-(propylthio)-3 .ff- [l,2,3]triazolo[4,5-i/]pyrimidin-3-yl)-2,3-dihydroxycyclopentyl)oxy)acetate;
  • Example 54 Methyl 2-(((lS,2S,3S,4R)-4-(7-(((lR,2S)-2-(3,4-difluorophenyl)- cyclopropyl)amino)-5-(propylt o)-3H-[l,2,3]triazolo[4,5-d]pyriirjidin-3-yl)-2,3- dihydiOxycyclopentyl) oxy) acetate
  • Example 54a Methyl 2-(((lS,2S,3S,4R)-4-(7-(((lR,2S)-2-(3,4-difluo)
  • Example 55a Preparation of (lS,2S,3R,5S)-3-(7-((lR,2S)-2-(3,4-difluorophenyl)cyclo- propylamino)-5 (propylthio)-3H-[l ,2,3]triazolo[4,5-d]pyrirnidin-3-yl)-5-(2-hydroxy- ethoxy)cyclo pentane -1,2-diol (Ticagrelor).
  • Example 56a Preparation of benzyl (3aR, 4S,6R,6aS)-4-(2-hydroxyethoxy)-tetrahydro- 2,2-dimethyl-3aH-cyclopenta[d][l,3]dioxol-6-ylcarbamate
  • Example 57a Preparation of 2-((3aS,4R,6S,6aR)-4-amino-tetrahydro-2,2-dimethyl-3aH- cyclopenta[d][l,3]dioxol-6-yloxy)ethanol, oxalic acid salt (1 :1).
  • Example 58a Preparation of 2-((3aS,4R,6S,6aR)-4-ammo-tetrahydro-2 > 2-dimethyl-3aH- cyclopenta[d][l,3]dioxol-6-yloxy)ethanol.
  • Example 59 Preparation of N-(4-cliloiO-6-(((3aS,4R,6S,6aR)-6-(2-liydiOxyethoxy)-2,2- dimethyl tetrahydro-3aH-cyclopenta[d] [1 ,3]dioxol-4-yl)amino)-2-(propyltliio) pyrimidin- 5-yl) formamide
  • Example 59 Preparation of N-(4-chloro-6-(((3aS,4R,6S,6aR)-6-(2-hydroxyethoxy)-2,2- dimethyl tetrahydro-3aH-cyclopenta[d][l,3]dioxol-4-yl)ammo)-2-(jpropylthio) pyrimidin- 5-yl) formamide
  • Example 60 Preparation of N-(4-chloro-6-(((3aS,4R,6S,6aR)-6-(2-hydroxyethoxy)-2,2- dimethyl tetrahydro-3 aH-cyclopenta[d] [ 1 ,3] dioxol-4-yl)amino)-2-(propylthio) pyrimidin- 5-yl) formamide
  • Example 60a Preparation of N-(4-chloro-6-(((3aS,4R,6S,6aR)-6-(2-hydroxyethoxy)-2,2- dimethyl tetrahydro-3aH-cyclopenta[d] [1 ,3]dioxol-4-yl)amino)-2-(propylthio) pyrimidin- 5-yl) formamide
  • Example 62 Preparation of (lS > 2S,3R,5S)-3-(7-((lR,2S)-2-(3,4-difluorophenyl) cyclopropyl amino)-5 (propyltMo)-3H-[l,2,3]triazolo[4,5-d]pyrmiidin-3-yl)-5-(2- hydroxyethoxy) cyclopentane-l,2-diol (Ticagreior)
  • Example 62a Preparation of (lS,2S,3R,5S)-3-(7-((lR,2S)-2-(3,4-difluorophenyl) cyclopropyl arnino)-5 (propylthio)-3H-[l ,2,3]rriazolo[4,5-d]pyrimidin-3-yl)-5-(2- hydroxyethoxy) cyclopentane- 1 ,2-diol (Ticagrelor)
  • reaction mixture is then cooled to 0-5°C and sodium nitrite (5.89g) is dissolved in water (12 mL) and added to the reaction mixture slowly dropwise.
  • the reaction mixture is stirred at 0-5°C for lhr.
  • the reaction mixture is then diluted with water (100 mL) and extracted with ethyl acetate (250 mL).
  • the organic layer is washed with brine (100 mL), sodium bicarbonate solution (100 mL) and finally with brine (lOOmL).
  • the organic layer is concentrated under reduced pressure and the resulting residue is crystallized from MTBE to provide compound XII (22.46g, 81%).

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Carbon And Carbon Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

L'invention concerne de nouveaux intermédiaires et procédés pour la préparation du ticagrelor décrit dans cette demande de brevet.
PCT/US2012/032497 2011-04-06 2012-04-06 Nouveaux intermédiaires et procédés pour la préparation du ticagrelor Ceased WO2012138981A2 (fr)

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BR112013025680A BR112013025680A2 (pt) 2011-04-06 2012-04-06 Novos intermediários e processos para preparar ticagrelor
CA2832570A CA2832570A1 (fr) 2011-04-06 2012-04-06 Nouveaux intermediaires et procedes pour la preparation du ticagrelor
US14/009,788 US9056838B2 (en) 2011-04-06 2012-04-06 Intermediates and processes for preparing Ticagrelor

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WO2014139489A1 (fr) 2013-03-14 2014-09-18 Zentiva K.S. Procédé perfectionné pour la synthèse de ticagrelor et nouveaux intermédiaires de la synthèse de ticagrelor
WO2014150258A1 (fr) * 2013-03-15 2014-09-25 Global Blood Therapeutics, Inc. Composés et ses utilisations pour la modulation de l'hémoglobine
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WO2015067230A1 (fr) 2013-11-08 2015-05-14 Zentiva, K.S. Procédé de production et nouvelle forme cristalline d'un intermédiaire pour la synthèse du ticagrelor
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US9604999B2 (en) 2013-03-15 2017-03-28 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US9604991B2 (en) 2013-06-24 2017-03-28 Suzhou Miracpharma Technology Co., Ltd. Preparation method of ticagrelor and intermediates thereof
WO2017118633A1 (fr) * 2016-01-05 2017-07-13 Amneal Pharmaceuticals Company Gmbh Forme cristalline de ticagrelor
US9776960B2 (en) 2013-03-15 2017-10-03 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
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US9981939B2 (en) 2013-03-15 2018-05-29 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
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US10011605B2 (en) 2014-06-18 2018-07-03 Flamma Spa Process for the preparation of triazolo[4,5-D] pyrimidine cyclopentane compounds
US10017491B2 (en) 2013-03-15 2018-07-10 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
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US10137118B2 (en) 2014-02-07 2018-11-27 Global Blood Therapeutics, Inc. Crystalline polymorphs of the free base of 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde
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US11020382B2 (en) 2015-12-04 2021-06-01 Global Blood Therapeutics, Inc. Dosing regimens for 2-hydroxy-6-((2-(1-isopropyl-1h-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde
US11053195B2 (en) 2013-03-15 2021-07-06 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
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Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TWI229674B (en) 1998-12-04 2005-03-21 Astra Pharma Prod Novel triazolo[4,5-d]pyrimidine compounds, pharmaceutical composition containing the same, their process for preparation and uses
WO2016038520A1 (fr) * 2014-09-08 2016-03-17 Sun Pharmaceutical Industries Limited Procédés pour la préparation de ticagrelor et ses intermédiaires
CN119080782A (zh) * 2024-10-10 2024-12-06 重庆普佑生物医药有限公司 替卡格雷的合成方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000034283A1 (fr) 1998-12-04 2000-06-15 Astrazeneca Ab Nouveaux composes de triazolo(4,5-d)pyrimidine

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0013488D0 (en) * 2000-06-02 2000-07-26 Astrazeneca Ab Chemical compound
US20110124634A1 (en) 2008-05-13 2011-05-26 Poniard Pharmaceuticals, Inc. Bioactive compounds for treatment of cancer and neurodegenerative diseases
ES2558843T3 (es) * 2008-09-09 2016-02-09 Astrazeneca Ab Procedimiento para preparar [1S-[1-alfa,2-alfa,3-beta(1S*,2R*),5-beta]]-3-[7-[2-(3,4-difluorofenil)-ciclopropilamino]-5-(propiltio)-3H-1,2,3-triazolo[4,5-d]pirimidin-3-il]-5-(2-hidroxietoxi)ciclopentano-1,2-diol y a sus productos intermedios
ES2605625T3 (es) * 2009-07-27 2017-03-15 Auspex Pharmaceuticals, Inc. Moduladores de ciclopropilo del receptor P2Y12

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000034283A1 (fr) 1998-12-04 2000-06-15 Astrazeneca Ab Nouveaux composes de triazolo(4,5-d)pyrimidine

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
"Protective Groups in Organic Chemistry", 1973, PLENUM PRESS
T W GREENE; P G M WUTZ: "Protective Groups in Organic Synthesis", 1991, WILEY-INTERSCIENCE

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US10266551B2 (en) 2013-03-15 2019-04-23 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US11530191B2 (en) 2013-03-15 2022-12-20 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
WO2014150258A1 (fr) * 2013-03-15 2014-09-25 Global Blood Therapeutics, Inc. Composés et ses utilisations pour la modulation de l'hémoglobine
US10435393B2 (en) 2013-03-15 2019-10-08 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US9802900B2 (en) 2013-03-15 2017-10-31 Global Blood Therapeutics, Inc. Bicyclic heteroaryl compounds and uses thereof for the modulation of hemoglobin
US9604999B2 (en) 2013-03-15 2017-03-28 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US10315991B2 (en) 2013-03-15 2019-06-11 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
WO2014155389A3 (fr) * 2013-03-25 2015-01-15 Glenmark Pharmaceuticals Limited; Glenmark Generics Limited Procédé de préparation de ticagrelor
ITMI20130487A1 (it) * 2013-03-29 2014-09-30 Chemo Res S L Alchilazione selettiva di ciclopentilalcoli
WO2014154908A1 (fr) * 2013-03-29 2014-10-02 Chemo Research, S.L. Alkylation sélective d'alcools cyclopentyliques
CN104098553A (zh) * 2013-04-10 2014-10-15 江苏恒瑞医药股份有限公司 替格瑞洛的中间体及其制备方法和替格瑞洛的制备方法
CN104098553B (zh) * 2013-04-10 2017-11-28 江苏恒瑞医药股份有限公司 替格瑞洛的中间体及其制备方法和替格瑞洛的制备方法
CN107573333A (zh) * 2013-04-10 2018-01-12 江苏恒瑞医药股份有限公司 替格瑞洛的中间体及其制备方法和替格瑞洛的制备方法
CN107573333B (zh) * 2013-04-10 2019-10-18 江苏恒瑞医药股份有限公司 替格瑞洛的中间体及其制备方法和替格瑞洛的制备方法
US9359366B2 (en) 2013-04-10 2016-06-07 Jiangsu Hengrui Medicine Co., Ltd. Intermediate of Ticagrelor and preparation method therefor, and preparation method for Ticagrelor
JP2016515635A (ja) * 2013-04-10 2016-05-30 ジエンス ヘンルイ メデイシンカンパニー リミテッドＪｉａｎｇｓｕ Ｈｅｎｇｒｕｉ Ｍｅｄｉｃｉｎｅ Ｃｏ．，Ｌｔｄ． チカグレロルの中間体およびその製造法、およびチカグレロルの製造法
WO2014166324A1 (fr) 2013-04-10 2014-10-16 江苏恒瑞医药股份有限公司 Intermédiaire de ticagrélor et procédé de préparation de celui-ci, et procédé de préparation de ticagrélor
TWI634116B (zh) * 2013-04-10 2018-09-01 江蘇恆瑞醫藥股份有限公司 替格瑞洛的中間體及其製備方法和替格瑞洛的製備方法
US9604991B2 (en) 2013-06-24 2017-03-28 Suzhou Miracpharma Technology Co., Ltd. Preparation method of ticagrelor and intermediates thereof
CN104250251B (zh) * 2013-06-25 2017-05-17 上海京新生物医药有限公司 一种替格瑞洛的制备方法
CN104250251A (zh) * 2013-06-25 2014-12-31 上海京新生物医药有限公司 一种替格瑞洛的制备方法
CN103288836A (zh) * 2013-06-27 2013-09-11 苏州明锐医药科技有限公司 替卡格雷的制备方法
CN104341402A (zh) * 2013-07-23 2015-02-11 博瑞生物医药技术(苏州)有限公司 一种制备替卡格雷中间体的方法
CN104341402B (zh) * 2013-07-23 2018-04-27 博瑞生物医药（苏州）股份有限公司 一种制备替卡格雷中间体的方法
WO2015037016A3 (fr) * 2013-09-10 2015-06-04 Laurus Labs Private Limited Procédé amélioré de préparation de ticagrelor et d'intermédiaires de celui-ci
CN103524429B (zh) * 2013-09-28 2015-08-19 银杏树药业(苏州)有限公司 一种替格瑞洛及其新的中间体的制备方法
CN103524429A (zh) * 2013-09-28 2014-01-22 银杏树药业(苏州)有限公司 一种替格瑞洛及其新的中间体的制备方法
CN105940003A (zh) * 2013-11-08 2016-09-14 赞蒂瓦有限合伙公司 替格瑞洛合成中间物的制备方法和新颖结晶形式
WO2015067230A1 (fr) 2013-11-08 2015-05-14 Zentiva, K.S. Procédé de production et nouvelle forme cristalline d'un intermédiaire pour la synthèse du ticagrelor
US10450269B1 (en) 2013-11-18 2019-10-22 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
CN104744424B (zh) * 2013-12-27 2018-12-25 博瑞生物医药（苏州）股份有限公司 一种替卡格雷中间体的制备方法
CN104744424A (zh) * 2013-12-27 2015-07-01 博瑞生物医药技术(苏州)有限公司 一种替卡格雷中间体的制备方法
US11452720B2 (en) 2014-02-07 2022-09-27 Global Blood Therapeutics, Inc. Crystalline polymorphs of the free base of 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde
US10137118B2 (en) 2014-02-07 2018-11-27 Global Blood Therapeutics, Inc. Crystalline polymorphs of the free base of 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde
US10722502B2 (en) 2014-02-07 2020-07-28 Global Blood Therapeutics, Inc. Crystalline polymorphs of the free base of 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde
WO2015162630A1 (fr) 2014-04-25 2015-10-29 Anlon Chemical Research Organization Nouveaux procédés de préparation de triazolo[4,5-d]-pyrimidines, dont le ticagrelor, via de nouveaux intermédiaires et une nouvelle voie de synthèse
US10011605B2 (en) 2014-06-18 2018-07-03 Flamma Spa Process for the preparation of triazolo[4,5-D] pyrimidine cyclopentane compounds
CN104193748A (zh) * 2014-08-14 2014-12-10 严白双 一种替卡格雷的合成方法
WO2016116942A1 (fr) 2015-01-20 2016-07-28 Anlon Chemical Research Organization Nouveaux composés pharmaceutiques comprenant du ticagrélor avec des sels d'aspirine
WO2016117852A3 (fr) * 2015-01-22 2016-10-27 동아에스티 주식회사 Procédé pour la préparation du ticagrelor et nouveaux intermédiaires à cet effet
US11020382B2 (en) 2015-12-04 2021-06-01 Global Blood Therapeutics, Inc. Dosing regimens for 2-hydroxy-6-((2-(1-isopropyl-1h-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde
US11944612B2 (en) 2015-12-04 2024-04-02 Global Blood Therapeutics, Inc. Dosing regimens for 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde
WO2017118633A1 (fr) * 2016-01-05 2017-07-13 Amneal Pharmaceuticals Company Gmbh Forme cristalline de ticagrelor
CN105669681A (zh) * 2016-04-11 2016-06-15 成都华宇制药有限公司 一种替格瑞洛的合成方法
US10577345B2 (en) 2016-05-12 2020-03-03 Global Blood Therapeutics, Inc. Process for synthesizing 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzaldehyde
US10077249B2 (en) 2016-05-12 2018-09-18 Global Blood Therapeutics, Inc. Process for synthesizing 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzaldehyde
US10493035B2 (en) 2016-10-12 2019-12-03 Global Blood Therapeutics, Inc. Tablets comprising 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde
CN108084145A (zh) * 2017-12-12 2018-05-29 南通常佑药业科技有限公司 替卡格雷中间体及其制备方法
US11014884B2 (en) 2018-10-01 2021-05-25 Global Blood Therapeutics, Inc. Modulators of hemoglobin
CN110627765A (zh) * 2019-10-14 2019-12-31 浙江乐普药业股份有限公司 一种替卡格雷关键中间体的制备方法
CN111574494A (zh) * 2020-05-20 2020-08-25 黑龙江鑫创生物科技开发有限公司 一种微通道反应器合成替格瑞洛中间体的方法
CN111848632A (zh) * 2020-09-07 2020-10-30 河南师范大学 一种血小板聚集抑制剂替格瑞洛的制备方法
CN112724119B (zh) * 2020-12-30 2022-05-03 江苏恒沛药物科技有限公司 一种替卡格雷关键中间体的合成方法
CN112724119A (zh) * 2020-12-30 2021-04-30 江苏恒沛药物科技有限公司 一种替卡格雷关键中间体的合成方法
CN115894430A (zh) * 2022-11-24 2023-04-04 四川青木制药有限公司 替格瑞洛关键中间体的制备方法
CN116535384A (zh) * 2023-04-17 2023-08-04 重庆普佑生物医药有限公司 替卡格雷中间体的制备方法

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